Clay F. Semenkovich, M.D.

Herbert S. Gasser Professor
Internal Medicine
Endocrinology/Metabolism and Lipid Research
Cell Biology and Physiology

Biochemistry, Biophysics, and Structural Biology Program
Molecular Genetics and Genomics Program

  • 314-362-7617

  • 314-362-4453

  • 314-362-7641

  • 8127

  • 842 Southwest Tower

  • csemenko@wustl.edu

  • aging, atherosclerosis, diabetes, lipids, obesity

  • Molecular and cell biology of atherosclerosis and diabetes

Research Abstract:

We study lipid metabolism and how it promotes atherosclerosis in the setting of obesity, insulin resistance and diabetes. Our work is translational, spanning cultured cells, animal models and humans.

Fats are partitioned to tissues in highly regulated ways. Excess lipids directed to adipose tissue lead to obesity, a disorder associated with diabetes, insulin resistance, and heart disease. We have engineered mice with ectopic and inducible expression of uncoupling protein-1 (UCP-1) in specific tissues. UCP-1 is an inner mitochondrial membrane anion transporter that uncouples respiration and oxidative phosphorylation. These animals are being used to study the role of tissue-specific metabolism in age-related diseases including atherosclerosis and hypertension.

Fatty acid metabolism is controlled in part by the nuclear receptor peroxisome proliferator-activated receptor alpha (PPARalpha). We have demonstrated a role for this receptor in modulating risk for atherosclerosis, diabetes and hypertension in animal models. Using tissue-specific inactivation of the rate-limiting enzyme in fatty acid synthesis, fatty acid synthase (FAS), we have also provided evidence that FAS is responsible for the generation of the endogenous ligand responsible for activating PPARalpha . Ongoing studies in mice and humans are defining the physiologic role of FAS in specific tissues and defining how fatty acid metabolism modulates cardiovascular risk in humans.

Up to a quarter of Americans have some combination of abnormal lipids, high blood pressure, elevated blood sugar, and excess abdominal fat. Collectively, these conditions constitute the metabolic syndrome, which confers considerable risk for frank diabetes and cardiovascular disease. We have shown that a mutation in the kinase ATM, known to be responsible for the cancer-prone disease ataxia telangiectasia, contributes to features of the metabolic syndrome in mice. Low dose, intermittent administration of the anti-malarial drug chloroquine activates ATM and improves metabolic abnormalities in mice. Mechanistic studies in animal models and clinical trials in humans are testing the hypothesis that ATM activation ameliorates the metabolic syndrome.

Selected Publications:

Chakravarthy MV, Lodhi IJ, Yin L, et al. Identification of a physiologically relevant endogenous ligand for PPARalpha in liver. Cell 2009 138:476-488.

Gates AC, Bernal-Mizrachi C, Chinault SL et al. Respiratory uncoupling in skeletal muscle delays death and diminishes age-related disease. Cell Metabolism 2007 6:497-505-102.

Chakravarthy MV, Zhu Y, López M, et al. Brain fatty acid synthase activates PPARalpha to maintain energy homeostasis. J Clin Invest 2007 117:2539-2552.

Schneider JG, Finck BN, Ren J, et al. ATM-dependent suppression of stress signaling reduces vascular disease in metabolic syndrome. Cell Metabolism 2006 4:377-389.

Bernal-Mizrachi C, Gates AC, Weng S, et al. Vascular respiratory uncoupling increases blood pressure and atherosclerosis. Nature 2005 435:502-506.

Last Updated: 8/4/2011 12:13:06 PM

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